CD44 Deficiency Attenuates Chronic Murine Ileitis

Abstract

Background & Aims Lymphocyte recruitment to sites of inflammation requires the sequential engagement of adhesion molecules and chemokine receptors. In the current studies we analyzed the role of CD44 for the development of chronic small-intestinal inflammatory infiltrates in vivo. Methods By using a tumor necrosis factor (TNF)-driven model of chronic ileitis (ie, B6.129P-TNFΔAU-rich element [ARE]) that recapitulates many features of Crohn’s disease, we noticed dynamic changes in the expression and functional state of CD44 and its ligand hyaluronan via enzyme-linked immunosorbent assay, real-time reverse-transcription polymerase chain reaction, immunohistochemistry, and flow cytometry. In addition, we assessed the role of lymphocyte populations during induction of ileitis through adoptive transfer studies, and generated CD44-deficient TNFΔARE mice to assess the role of CD44 for development of ileitis. Results Soluble hyaluronan levels and expression of hyaluronan synthase-1 were increased in TNFΔARE mice. This coincided with increased expression of CD44 (including variant 7) and reactivity towards hyaluronan on CD4+ T cells. CD44 was spatially co-localized with the gut-homing integrin α4β7, spatially linking lymphocyte rolling with arrest. These cells had an effector phenotype because they lacked L-selectin and a higher proportion in diseased mice produced TNF and interleukin-2 compared with wild-type littermates. Lastly, CD4+ but not CD8+ T cells conferred ileitis to RAG−/− recipients and deficiency of one or both alleles of the CD44 gene resulted in attenuation of the severity of ileitis in TNFΔARE mice. Conclusions Our findings support an important role of CD44 expressed by CD4+ and CD8+ for development of ileitis mediated by TNF overproduction.

Lactobacillus reuteri DSM 17938 differentially modulates effector memory T cells and Foxp3+ regulatory T cells in a mouse model of necrotizing enterocolitis

“…ϩ Tem cells express high levels of CD44, which is involved in Th1-driven inflammation (39), including recirculation of T cells to inflammatory sites and chemotaxis (8). CD44 extracted from Th1 cells was found to bind soluble E-selectin in vitro and cooperated with P-selectin glycoprotein ligand-1 in mediating a rolling interaction between T lymphocytes and the vascular endothelium.…”

“…A combined absence of CD44 and P-selectin glycoprotein ligand-1 impairs inflammatory T cell recruitment (39). CD4 ϩ CD44 ϩ T cells were found to have effector function and phenotype, to show enhanced reactivity to CD44 ligand hyaluronan, to produce inflammatory cytokines such as TNF-␣ and IL-2, and to be essential for the induction of ileitis in RAG Ϫ/Ϫ mice (8). Conversely, CD44 deficiency attenuated chronic murine ileitis (8).…”

“…CD4 ϩ CD44 ϩ T cells were found to have effector function and phenotype, to show enhanced reactivity to CD44 ligand hyaluronan, to produce inflammatory cytokines such as TNF-␣ and IL-2, and to be essential for the induction of ileitis in RAG Ϫ/Ϫ mice (8). Conversely, CD44 deficiency attenuated chronic murine ileitis (8). In addition to expressing CD44, the majority of effector/memory cells express low levels of CD45RB and L-selectin (59).…”

“…CD44 is upregulated concomitant with the activation of naive T lymphocytes during invasive microbial infection (2). Recent studies showed that CD44 deficiency attenuates murine ileitis (8). The adhesion molecule CD44, as a marker for activated effector CD4 ϩ T cells in inflamed tissues, potentiates T cell activation and maintenance of T cell memory function (3 Probiotic supplementation has been associated with a significantly decreased risk of NEC in preterm very-low-birth-weight infants (62).…”

Osteopontin Mediates Citrobacter rodentium-Induced Colonic Epithelial Cell Hyperplasia and Attaching-Effacing Lesions

“…47 Defects in migration of cells in the absence of OPN, such as shown for neutrophil recruitment 35 and macrophage chemotaxis, 34 are mediated by impaired cytoskeletal responses, likely due to a reduction in association with the CD44 receptor. 39,48 Furthermore, while unchallenged OPN-null fibroblasts exhibit a normal cytoskeleton, stressed cells show defects in rearrangements of the actin cytoskeleton and in the ability to form stress fibers and focal adhesions. 49 Similarly, our findings suggest a role for OPN in modulating host responses to intestinal bacteria in infected epithelial cells, which then specifi-cally impacts on the development of mucosal injury and responses to enteric pathogens.…”